State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Department of Head and Neck Surgery, Sichuan Cancer Institute, Sichuan Cancer Center, Sichuan Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610000, P.R. China.
Oncol Rep. 2021 Mar;45(3):1011-1022. doi: 10.3892/or.2021.7939. Epub 2021 Jan 18.
High expression of δ‑like ligand 4 (Dll4) is reportedly related to the invasion, metastasis, and clinical prognosis of various malignant tumours. Our previous study revealed that collective cell invasion was a common pattern in salivary adenoid cystic carcinoma (SACC). However, the roles of the Dll4/Notch1 signalling pathway in the collective invasion of SACC remain unclear. The present study revealed that Dll4 expression was higher at the invasive front of SACC, and that this upregulation was associated with solid tumour type, high TNM grade, and high rates of metastasis and recurrence. Furthermore, the expression levels of Notch1 and Dll4 were positively correlated at the invasive front, and a three‑dimensional (3D) culture model revealed that leader cells showed high expression of Dll4, while follower cells showed high expression of Notch1. Moreover, silencing of Dll4 expression using small interfering RNA reduced the migration, invasion, and collective invasion of SACC cells, and these abilities were rescued by Notch1 overexpression. Finally, SACC collective invasion was increased via the Dll4/Notch1 signalling pathway in experiments that involved a stiff 3D gel, hypoxia and co‑culture with human endothelial cells. These findings indicated that the Dll4/Notch1 signalling pathway may be involved in the collective invasion of SACC, which may help to provide possible targets for the treatment of SACC.
δ-样配体 4（Dll4）的高表达与各种恶性肿瘤的侵袭、转移和临床预后有关。我们之前的研究表明，细胞集体侵袭是唾液腺腺样囊性癌（SACC）的一种常见模式。然而，Dll4/Notch1 信号通路在 SACC 细胞集体侵袭中的作用尚不清楚。本研究显示，Dll4 在 SACC 的侵袭前沿表达较高，而上调与实体瘤类型、高 TNM 分级、高转移和复发率有关。此外，在侵袭前沿 Notch1 和 Dll4 的表达水平呈正相关，三维（3D）培养模型显示，先导细胞高表达 Dll4，而跟随细胞高表达 Notch1。此外，用小干扰 RNA 沉默 Dll4 表达可降低 SACC 细胞的迁移、侵袭和集体侵袭能力，而 Notch1 过表达可挽救这些能力。最后，通过在刚性 3D 凝胶、低氧和与人内皮细胞共培养的实验中，Dll4/Notch1 信号通路增加了 SACC 的集体侵袭。这些发现表明，Dll4/Notch1 信号通路可能参与 SACC 的集体侵袭，这可能有助于为 SACC 的治疗提供可能的靶点。
